Plasma urate concentration and risk of coronary heart disease: a Mendelian randomisation analysis.
Open accessAbstract
BACKGROUND: Increased circulating plasma urate concentration is associated with an increased risk of coronary heart disease, but the extent of any causative effect of urate on risk of coronary heart disease is still unclear. In this study, we aimed to clarify any causal role of urate on coronary heart disease risk using Mendelian randomisation analysis. METHODS: We first did a fixed-effects meta-analysis of the observational association of plasma urate and risk of coronary heart disease. We then used a conventional Mendelian randomisation approach to investigate the causal relevance using a genetic instrument based on 31 urate-associated single nucleotide polymorphisms (SNPs). To account for potential pleiotropic associations of certain SNPs with risk factors other than urate, we additionally did both a multivariable Mendelian randomisation analysis, in which the genetic associations of SNPs with systolic and diastolic blood pressure, HDL cholesterol, and triglycerides were included as covariates, and an Egger Mendelian randomisation (MR-Egger) analysis to estimate a causal effect accounting for unmeasured pleiotropy. FINDINGS: In the meta-analysis of 17 prospective observational studies (166 486 individuals; 9784 coronary heart disease events) a 1 SD higher urate concentration was associated with an odds ratio (OR) for coronary heart disease of 1·07 (95% CI 1·04-1·10). The corresponding OR estimates from the conventional, multivariable adjusted, and Egger Mendelian randomisation analysis (58 studies; 198 598 individuals; 65 877 events) were 1·18 (95% CI 1·08-1·29), 1·10 (1·00-1·22), and 1·05 (0·92-1·20), respectively, per 1 SD increment in plasma urate. INTERPRETATION: Conventional and multivariate Mendelian randomisation analysis implicates a causal role for urate in the development of coronary heart disease, but these estimates might be inflated by hidden pleiotropy. Egger Mendelian randomisation analysis, which accounts for pleiotropy but has less statistical power, suggests there might be no causal effect. These results might help investigators to determine the priority of trials of urate lowering for the prevention of coronary heart disease compared with other potential interventions. FUNDING: UK National Institute for Health Research, British Heart Foundation, and UK Medical Research Council.
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Estimates from the MR-Egger method are particularly affected by outlying and influential datapoints and are prone to be imprecise, particularly when the variant-exposure associations are all similar in magnitude.
“Estimates from the MR-Egger method are particularly affected by outlying and influential datapoints 90 , and are prone to be imprecise, particularly when the variant—exposure associations are all similar in magnitude.”
From Guidelines for performing Mendelian randomization investigations (2020) · cites this paper as [90]
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References 27 · Cited by 132
- Authors
- White, J., Sofat, R., Hemani, G., Shah, T., Engmann, J., Dale, C., Shah, S., Kruger, F. A., Giambartolomei, C., Swerdlow, D. I., Palmer, T., McLachlan, S., Langenberg, C., Zabaneh, D., Lovering, R., Cavadino, A., Jefferis, B., Finan, C., Wong, A., Amuzu, A., Ong, K., Gaunt, T. R., Warren, H., Davies, T.-L., Drenos, F., Cooper, J., Ebrahim, S., Lawlor, D. A., Talmud, P. J., Humphries, S. E., Power, C., Hypponen, E., Richards, M., Hardy, R., Kuh, D., Wareham, N., Ben-Shlomo, Y., Day, I. N., Whincup, P., Morris, R., Strachan, M. W. J., Price, J., Kumari, M., Kivimaki, M., Plagnol, V., Whittaker, J. C., Smith, G. D., Dudbridge, F., Casas, J. P., Holmes, M. V., & Hingorani, A. D.
- Affiliations
- University College London (GB)
- University of Bristol (GB)
- Farr Institute (GB)
- London School of Hygiene & Tropical Medicine (GB)
- The University of Queensland (AU)
- University of Warwick (GB)
- University of Edinburgh (GB)
- University of Cambridge (GB)
- British Heart Foundation (GB)
- The Royal Free Hospital (GB)
- Wellcome Sanger Institute (GB)
- MRC Unit for Lifelong Health and Ageing (GB)
- Queen Mary University of London (GB)
- University of London (GB)
- Western General Hospital (GB)
- GlaxoSmithKline (United Kingdom) (GB)
- University of Oxford (GB)
- Corresponding author
- White, Jon
- Holmes, Michael V
- ORCID
- White, Jon
- Sofat, Reecha
- Hemani, Gibran
- Shah, Tina
- Engmann, Jorgen
- Dale, Caroline
- Shah, Sonia
- Giambartolomei, Claudia
- Swerdlow, Daniel I
- Palmer, Tom
- McLachlan, Stela
- Langenberg, Claudia
- Zabaneh, Delilah
- Lovering, Ruth
- Cavadino, Alana
- Jefferis, Barbara
- Finan, Chris
- Wong, Andrew
- Ong, Ken
- Gaunt, Tom R
- Warren, Helen
- Drenos, Fotios
- Cooper, Jackie
- Ebrahim, Shah
- Lawlor, Debbie A
- Talmud, Philippa J
- Humphries, Steve E
- Power, Christine
- Richards, Marcus
- Hardy, Rebecca
- Kuh, Diana
- Wareham, Nicholas
- Whincup, Peter
- Morris, Richard
- Strachan, Mark W J
- Plagnol, Vincent
- Whittaker, John C
- Smith, George Davey
- Dudbridge, Frank
- Casas, Juan P
- Holmes, Michael V
- Hingorani, Aroon D
- Venue
- The Lancet Diabetes & Endocrinology
- Publisher
- Elsevier BV
- Published
- 2016-04
- Volume
- 4
- Issue
- 4
- Pages
- 327-336
- ISSN
- 2213-8587 (ISSN-L)
- PMC
- PMC4805857
- OpenAlex
- W2266722857
- Cited by
- 132
- References
- 27
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 8 · 2023: 6 · 2022: 14 · 2021: 16 · 2020: 15 · 2019: 14 · 2018: 18 · 2017: 23 · 2016: 6
- FWCI
- 20.40
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- The Lancet Diabetes & Endocrinology (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Explore Bristol Research (publishedVersion, cc-by)
- St George's Online Research Archive (St George's University of London) (acceptedVersion)
- Leicester Research Archive (University of Leicester) (acceptedVersion, other-oa)
- Open Access at Essex (University of Essex) (acceptedVersion)
- LSHTM Research Online (London School of Hygiene and Tropical Medicine) (acceptedVersion)
- Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion, cc-by)
- Lancaster EPrints (Lancaster University) (submittedVersion, public-domain)
- Research Portal (King's College London) (submittedVersion, public-domain)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by)
- Bristol Research (University of Bristol) (submittedVersion, cc-by)
- UniSA Research Outputs Repository (University of South Australia) (submittedVersion, other-oa)
- UCL Discovery (University College London) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Spiral (Imperial College London) (submittedVersion, other-oa)
- Funders
- Bayer, United Kingdom (G0500877)
- British Heart Foundation (RG/13/16/30528, RG/10/12/28456)
- Agency for Healthcare Research and Quality (HS06516)
- National Institutes of Health (NHLBI 33014)
- Wellcome Trust (068545/Z/02)
- National Institute for Health Research
- CAPS Research
- Ministère de l'Education Nationale, de l'Enseignement Superieur et de la Recherche
- Stroke Association
- National Institute on Aging (G0000934, MC_UU_12019/1, 5RO1AG13196)
- National Heart, Lung, and Blood Institute (5RO1 HL036310)
- John D. and Catherine T. MacArthur Foundation (AG1764406S1)
- Diabetes UK (MR_UU_12013/1, 10/0003985, MR_UU_12013/5, MR_UU_12013/8)
- Chest Heart and Stroke Scotland (Res03/A75)
- Chief Scientist Office (RG/97006, CZB/4/672, K/OPR/2/2/D320, 057762)
- Pfizer
- Fifth Framework Programme (018996)
- Medical Research Council (G0902037, RG/07/008/23674)
- Topics
- Health Sciences › Medicine › Nephrology › Gout, Hyperuricemia, Uric Acid
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Paraoxonase enzyme and polymorphisms
- Keywords
- plasma urate, hyperuricemia, coronary artery disease, causal effects, urate-lowering therapy, pleiotropy, blood pressure, HDL cholesterol, triglycerides, MR-Egger, urate-lowering drugs, cardiovascular disease prevention, genetic instruments, heterogeneity
- MeSH terms
- Coronary Disease, Humans, Risk Factors, Uric Acid, Meta-Analysis as Topic, Mendelian Randomization Analysis, Observational Studies as Topic
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